The present invention relates to sustained release matrix preparations containing tramadol or a pharmaceutically acceptable salt thereof as the therapeutically active agent.
Sustained release preparations are known to those skilled in the art to achieve a slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. Preferably such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.
An important aspect of the manufacture, regulatory review and approval of all dosage forms concerns their stability over extended periods of time. The stability data obtained with regard to a particular dosage form directly affects its shelf-life. The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. Stability study requirements are covered, e.g., in the Good Manufacturing Practices (GMPs), the U.S.P., as well as in the regulatory requirements of the country where approval to market a dosage form is being sought. In the United States, a request to test, and eventually market, a drug or a drug formulation may be made via a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA) or an Investigational New Drug Applications (IND).
The agents used in sustained release dosage formulations often present special problems with regard to their physical stability during storage. For example, waxes which have been used in such formulations are known to undergo physical alterations on prolonged standing. Precautions may be taken to stabilize waxes at the time of manufacture or to prevent the change from occurring. Fats and waxy materials when used in purified states are known to crystallize in unstable forms, causing unpredictable variations in availability rates during stability testing at the time of manufacture and during later storage.
It is known that certain strategies can be undertaken to obtain stabilized controlled release formulations in many cases, such as insuring that the individual agents are in a stable form before they are incorporated into the product, and that processing does not change this condition, retarding the instability by including additional additives, and inducing the individual agents of the dosage form to reach a stable state before the product is finally completed.
It is also recognized that the moisture content of the product can also influence the stability of the product. Changes in the hydration level of a polymeric film, such as the ethyl celluloses, can alter the rate of water permeation and drug availability. Also, binders such as acacia are known to become less soluble when exposed to moisture and heat. However, moisture content of a product can be controlled fairly successfully by controls in the processing method and proper packaging of the product.
Hydrophobic polymers such as certain cellulose derivatives, zein, acrylic resins, waxes, higher aliphatic alcohols, and polylactic and polyglycolic acids have been used in the prior art to develop controlled release dosage forms. Methods of using these polymers to develop controlled release dosage forms such as tablets, capsules, suppositories, spheroids, beads or microspheres are to overcoat the individual dosage units with these hydrophobic polymers. It is known in the prior art that these hydrophobic coatings can be applied either from a solution, suspension or dry. Since most of these polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) and evaporating off the solvent.
The use of organic solvents in the preparation of hydrophobic coatings is considered undesirable because of inherent problems with regard to flammability, carcinogenicity, environmental concerns, and safety in general. It considered very desirable in the art, however, to provide a controlled release coating derived from aqueous dispersions of a hydrophobic material. Unfortunately, such formulations were prone to changes in dissolution characteristics upon storage, rendering such formulations unsuitable for oral sustained release dosage forms containing therapeutically active agents. Stabilized controlled release formulations which utilize ethyl cellulose as a controlled release coating are described in the assignee""s previous U.S. Pat. Nos. 5,273,760 and 5,472,712, hereby incorporated by reference. Stabilized controlled release formulations which utilize one or more acrylic polymers as a controlled release coating are described in the assignee""s previous U.S. Pat. Nos. 5,286,493; 5,580,578; and 5,639,476, hereby incorporated by reference.
Sustained release oral dosage forms in which the therapeutically active agent is incorporated into a matrix containing one or more hydrophobic and/or hydrophilic materials are also well known to those skilled in the art. In this regard, reference is made to U.S. Pat. No. 3,965,256 (Leslie) which is directed to slow release pharmaceutical compositions comprising a combination of a higher aliphatic alcohol and a hydrated hydroxy-alkyl cellulose; and U.S. Pat. Nos. 4,861,598 and 4,970,075 (Oshlack, et al.), wherein the release of therapuetically active agents from controlled release bases is extended by using a combination of a higher aliphatic alcohol and an acrylic resin as the base material.
Melt granulation techniques have also been suggested to provide controlled release formulations. Melt granulation usually involves mechanically working an active ingredient in particulate form with one or more suitable binders and/or pharmaceutically acceptable excipients in a mixer until one or more of the binders melts and adheres to the surface of the particulate, eventually building up granules. This technique has been utilized in the exemplification of sustained release oral tramadol dosage formulations, as set forth in the assignee""s U.S. Pat. No. 5,591,452, hereby incorporated by reference.
PCT International Publication No. WO 92/06679, incorporated by reference, discloses melt granulating methods for producing pellets containing therapeutically active substances. The method includes mechanically working a mixture containing the active substance in cohesive form with a binder having a melting point of 40-100xc2x0 C., while supplying sufficient energy to melt the binder and form xe2x80x9covermoistxe2x80x9d spherical pellets and thereafter adding an additional cohesive substance while maintaining the mechanical working to finally produce dry pellets.
PCT International Publication No. WO 93/18753, incorporated by reference, also discloses another melt extrusion process for preparing sustained release pellets. This method includes pelletizing a mixture containing drug in finely divided form and a binder which includes one or more water-insoluble-wax-like binder substances with a melting point above 40xc2x0 C. using a high shear mixer.
It is an object of the present invention to provide an oral sustained release solid dosage form of tramadol suitable for at least twelve-hourly (e.g. up to twenty-four hourly) administration for the treatment of pain.
It is an object of the present invention to provide sustained release tramadol formulations which provide a stable dissolution, even after exposure to accelerated storage conditions or to prolonged storage at room temperature.
It is an object of the present invention to provide a method of preparing a sustained release tablet which includes tramadol as the drug which tablet provides a stable dissolution profile of the drug when plated in an environment of use, despite exposure to accelerated storage conditions.
A further object of the present invention is to provide a stabilized sustained release tramadol formulation wherein the sustained release is provided via a matrix of a hydrophobic material comprising a wax-like substance and the drug, wherein the wax-like substance is softened or melted during the preparation of the matrix, and which formulation provides a stable dissolution of an active agent contained in the formulation, despite exposure to accelerated storage conditions such that the dissolution would be deemed acceptable by a governmental regulatory agency such as the U.S. Food and Drug Administration (xe2x80x9cFDAxe2x80x9d) for purposes of according expiration dating.
It is another object of the present invention to provide a method of preparing a sustained release tramadol tablet containing a hydrophobic material which comprises a wax-like substance such that there is a stable dissolution profile of the tramadol when placed in an environment of use, despite exposure to accelerated storage conditions.
These objects and others have been accomplished by the present invention, which relates in part to a stabilized sustained release oral solid dosage form or formulation containing tramadol or a pharmaceutically acceptable salt or complex thereof in a matrix comprising a hydrophobic material which has been softened or melted during the preparation of the dosage form, which dosage form after preparation of the matrix containing the tramadol is cured at a suitable temperature (e.g., a temperature above the glass transition temperature of the hydrophobic material (in the case of polymers) until an endpoint is reached at which the cured dosage form, when subjected to in-vitro dissolution, releases the tramadol in amounts which do not vary at any time point along the dissolution curve by more than about 20% of the total amount of tramadol released, when compared to the in-vitro dissolution of the formulation prior to curing.
The invention is further directed to a stabilized sustained release oral solid dosage form containing tramadol as the active agent, comprising an effective amount of tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a wax-like substance which was melted or softened during the preparation of said matrix. The solid dosage form is cured at a sufficient temperature and for a sufficient time such that an endpoint is reached at which said solid dosage form provides a stable dissolution profile. The endpoint is determined by comparing the dissolution profile of said solid dosage form immediately after curing to the dissolution profile of said solid dosage form after exposure to accelerated storage conditions of at least one month at 40xc2x0 C. and 75% relative humidity. The curing is preferably conducted at a temperature from about 35xc2x0 C. to about 65xc2x0 C., preferably from about 40xc2x0 C. to about 60xc2x0 C., preferably for a time period from about 4 to about 72 hours. In certain preferred embodiments, the curing is preferably conducted for a time period of about 24 hours or more, until the endpoint is reached. In certain embodiments, the curing is conducted at a temperature from about 45xc2x0 C. to about 55xc2x0 C. for a time period from about 4 to about 72 hours, preferably for a time period of about 24 hours, until the endpoint is reached. The wax-like substance may be selected from the group consisting of hydrogenated vegetable oil, hydrogenated castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, and mixtures thereof. The hydrophobic material may further comprise a hydrophobic polymerxe2x80x94selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof. Further, the matrix may contain a hydrophilic polymer, e.g., a cellulose ether, or other hydrophilic material. The sustained release dosage form may be in the form of a unit dose of multiparticulates, or a tablet.
In certain preferred embodiments, the matrix of the stabilized sustained release oral solid dosage form comprises tramadol, a higher aliphatic alcohol, and a hydrophobic polymer selected from the group consisting of acrylic polymers, alkylcelluloses and mixtures thereof. In other preferred embodiments, the matrix of the stabilized sustained release oral solid dosage form comprises tramadol and hydrogenated vegetable oil.
Another aspect of the invention provides a method of preparing a sustained release oral solid dosage form containing tramadol as the active ingredient. This method includes mixing tramadol together with a hydrophobic material and an optional binder to form a homogeneous mixture, heating the mixture and thereafter extruding and granulating the mixture. Thereafter the granulate is preferably compressed into tablets (after mixing with optional pharmaceutical excipients such as talc and a lubricant such as magnesium stearate), and the tablets cured as described herein. In alternative embodiments, the granulate (or the extrudate cut into appropriately sized particles) is cured as described herein and then the granulate is divided into suitable unit dosages of tramadol (e.g., filled into pharmaceutically acceptable gelatin capsules). In preferred embodiments, the curing is conducted at a temperature from about 35xc2x0 C. to about 65xc2x0 C., preferably about 40xc2x0 C. to about 60xc2x0 C., for a time period from about 4 to about 72 hours, preferably at least about 24 hours. In further preferred embodiments, the curing is conducted at a temperature from about 45xc2x0 C. to about 55xc2x0 C. for a time period from about 4 to about 72 hours, preferably at least about 24 hours.
The invention further relates to a process for preparing a stabilized sustained release oral solid dosage form containing tramadol as the active agent, comprising preparing a matrix comprising tramadol or a pharmaceutically acceptable salt thereof dispersed in a matrix of a hydrophobic material comprising a wax-like substance, wherein the wax-like substance is melted or softened during the preparation of said matrix; and thereafter curing the matrix at a sufficient temperature and for a sufficient time such that an endpoint is reached at which the matrix provides a stable dissolution profile. The endpoint is determined by comparing the dissolution profile of the matrix immediately after curing to the dissolution profile of the matrix after exposure to accelerated storage conditions of at least one month at 40xc2x0 C. and 75% relative humidity. The matrix may comprise a plurality of pharmaceutically acceptable particles (such as granules), or the matrix may comprise a tablet. In preferred embodiments, the matrix is compressed into a tablet. The process for preparing a stabilized sustained release oral solid dosage form containing tramadol in accordance with the present invention may be any process which includes a wax or wax-like material in the matrix, and where the wax or wax-like material is softened or melted during preparation of the dosage form. In certain preferred embodiments, the formulation is prepared by feeding tramadol and hydrophobic material, together with further optional pharmaceutical excipients, into an extruder at elevated temperatures sufficient to soften or melt the wax-like material; extruding the mixture; granulating the mixture; lubricating the granulate; and then optionally compressing the granulate into tablets. In other preferred embodiments, the formulations are prepared by spraying a hydrophobic polymer dispersion onto a mixture of tramadol and an inert diluent in a fluid bed dryer to obtain granulates; mixing molten wax-like substance into the granulates in a high shear mixer; passing the mixture through a screen and mixing with talc; lubricating the resultant material; and optionally compressing the lubricated granulates into tablets. In yet further preferred embodiments of the invention, the formulation is prepared by pouring molten wax-like substance onto the tramadol in a pharmaceutically suitable mixer; allowing the mixture to congeal and cool; and thereafter milling the mixture; lubricating the mixture; and compressing the lubricated granulation into tablets. In a further alternative preferred method, the formulations of the invention are prepared by melting and granulating a wax-like substance; hydrating a cellulose ether and granulating the same; blending the tramadol with either the granulated melt, the granulated cellulose ether, or a mixture thereof; drying the granules; and thereafter optionally mixing with an appropriate amount of a inert pharmaceutically acceptable diluent and compressing the mixture tablets.
In embodiments where the hydrophobic material comprises a hydrophilic or hydrophobic polymer in addition to the wax-like substance, the formulation may be prepared by (a) wet granulating the hydrophobic or hydrophilic polymer and optional diluents with or without the tramadol; (b) drying and sizing the resultant granulate; (c) combining said tramadol with the granulate if not previously accomplished in step (a); incorporating the wax-like substance in a molten state into the granules using a suitable mixer; (d) cooling and sizing the granules; and thereafter (e) optionally lubricating the granules compressing the lubricated granules into tablets.
In yet a further aspect of the invention, there is provided a method of treating a patient by administering the sustained release oral solid dosage forms of tramadol which provide a stable dissolution as described herein.
In preferred embodiments of the invention, the curing of the solid dosage form containing tramadol gradually slows the release of said active agent when exposed to an environmental fluid, such that the cured formulation provides a stabilized dissolution of tramadol which is unchanged after exposure to accelerated storage conditions, the stabilized dissolution being deemed appropriate by the United States Food and Drug Administration, the Committee on Proprietary Medicinal Products (xe2x80x9cCPMPxe2x80x9d) in Europe, and other similar Governmental Regulatory Authorities, for the purpose of according expiration dating for said formulation. The curing may continue, for example, for a sufficient period of time until a curing endpoint is reached to provide a stabilized dissolution of tramadol from the dosage form which is unchanged after exposure to accelerated storage conditions. The endpoint may be determined by comparing the dissolution profile of the formulation immediately after curing to the dissolution profile of the formulation after exposure to accelerated storage conditions, e.g., of one-three months at a temperature of 37xc2x0 C. and at a relative humidity of 80%.
In other preferred embodiments, the curing of the sustained release oral solid dosage form, after exposure to accelerated storage conditions of at least one month at 40xc2x0 C./75% RH, releases an amount of tramadol which does not vary at any given dissolution time point by more than about 20% of the total amount of tramadol released, when compared to in-vitro dissolution conducted prior to storage.
In other embodiments, the oral sustained release solid dosage form of tramadol, upon in-vitro dissolution testing, provides a band range after exposure to accelerated storage conditions which is not wider than about 20% at any point of time when compared to the dissolution profile prior to exposure to the accelerated storage conditions.
The terms xe2x80x9cstable dissolution profilexe2x80x9d and xe2x80x9ccuring endpointxe2x80x9d are defined for purposes of the present invention as meaning that the cured solid dosage form (e.g., tablet) reproducibly provides a release of the active agent (e.g., tramadol) when placed in an environment of use which is unchanged, even after exposing the cured formulation to accelerated storage conditions. Those skilled in the art will recognize that by xe2x80x9cunchangedxe2x80x9d it is meant that any change in the release of the active agent from the cured formulation would be deemed insignificant in terms of the desired effect. For pharmaceutical formulations, stability is determined by, e.g, a regulatory agency such as the Food and Drug Administration (FDA) in the U.S., or the Committee on Proprietary Medicinal Products (xe2x80x9cCPMPxe2x80x9d) in Europe, for the purpose of according an expiration date for the formulation.
By the phrase xe2x80x9caccelerated storage conditionsxe2x80x9d it is meant, e.g., storage conditions of elevated temperature and/or elevated relative humidity. Preferably, the phrase xe2x80x9caccelerated storage conditionsxe2x80x9d refers to storage conditions to which the final drug formulation is subjected for the purpose of obtaining regulatory approval (e.g., FDA approval in the U.S.) and an expiration date.
The term xe2x80x9cexpiration datexe2x80x9d is defined for purposes of the present invention as the date designating the time during which a batch of the product (e.g., the cured, coated substrate) is expected to remain within specification if stored under defined conditions, and after which it should not be used.
The term xe2x80x9cband rangexe2x80x9d for purposes of the present invention is defined as the difference in in-vitro dissolution measurements of the controlled release formulations when comparing the dissolution profile (curve) obtained by the formulation upon completion of the manufacturing of the coated product (prior to storage) and the dissolution profile obtained after the coated product is exposed to accelerated storage conditions, expressed as the change in percent of the active agent released from the coated product at any dissolution time point along the dissolution curves.
The term xe2x80x9csustained releasexe2x80x9d is defined for purposes of the present invention as the release of the drug (i.e., tramadol) at such a rate that blood (e.g., plasma) levels are maintained within the therapeutic range but below toxic levels over a period of time greater than 6 hours, more preferably for periods of about 12 hours (i.e., twice-a-day) or about 24 hours (i.e., once-a-day), or longer. The term sustained release is deemed to encompass the term xe2x80x9cprolonged releasexe2x80x9d as that term is used by the CPMP.
The term xe2x80x9ccuringxe2x80x9d is defined for purposes of the present invention as the heat treatment of the dosage form (or intermediate product) for purposes of obtaining a stabilized final oral pharmaceutical sustained release dosage form as defined above. When the formulations of the invention incorporate a polymer as part or all of the hydrophobic retarding agent, it will be appreciated by those skilled in the art that a heat treatment causes a curing effect and that the polymer possibly cross-links with itself into a more stable state. When the formulations of the invention do not incorporate a polymer but rather include a hydrophobic material such as, e.g., hydrogenated vegetable oil or stearyl alcohol, one skilled in the art will appreciate that the heat treatment is more akin to an annealing of the formulation rather than a curing of the polymer. However, for purposes of the present invention, the use of the term xe2x80x9ccuringxe2x80x9d is deemed to encompass both curing and/or annealing.